Pharmacologically active anilinobenzothiazoles

ABSTRACT

Anilinobenzothiazoles of the formula below and pharmaceutically acceptable acid addition salts thereof, wherein R is hydrogen or methoxy. The compounds have therapeutic value as antidepressants for warm-blooded animals.

United States Patent [191 Sharpe PHARMACOLOGICALLY ACTIVE ANlLlNOBENZOTl-IIAZOLES [75] Inventor: Christopher James Sharpe, Harrow Weald, England 173] Assignee: The Boots Company Limited,

Nottingham, England [22] Filed: Mar. 21, 1973 [21] ,Appl. No.: 343,565

[30] Foreign Application Priority Data Mar. 30, 1972 United Kingdom l50l8/72 [52] US. Cl 260/305; 424/270 [5 1] Int. Cl C07d 99/10 [58] Field of Search 260/305 [56] References Cited UNITED STATES PATENTS 2,040,928 5/1936 Engelmann 260/305 [451 July 29,1975

2,676,970 4/ l954 Steiger et al. 260/305 Primary Examiner-R. J. Gallagher Attorney, Agent, or Firm-DeLio and Montgomery [57] ABSTRACT NHQOCH CH JJ I S 4 Claims, No Drawings PHARMACOLOGICALLY ACTIVE ANILINOBENZOTHIAZOLES This invention relates to new chemical compounds with pharmacological activity. More particularly, the invention relates to new anilinobenzothiazoles of the formula I wherein R is hydrogen or methoxy, which possess antidepressant activity. Formula I encompasses two compounds, namely 5-methoxy-2-[4(Z-pyrrolidin-lylethoxy)anilinolbenzothiazole and 2-[4-(2-pyrrolidinl-ylethoxy)anilino]benzothiazole. These compounds are organic bases which form salts with inorganic and organic acids.

The compounds of formula I have properties consistent with their therapeutic value as antidepressants. Thus, when administered to warm-blooded animals in non-toxic doses by the oral or parenteral route, the compounds reverse reserpine-induced hypothermia, reverse reserpine-induced blepharoptosis, antagonise the sedative effect of tetrabenazine and inhibit the convulsant effect of leptazol.

In utilizing the therapeutic properties of the compounds of formula I, they may be administered as free bases or in the form of pharmaceutically acceptable acid addition salts thereof. Thus according to the present invention there are provided the new compounds of the hereinbefore defined formula I and pharmaceutically acceptable acid addition salts thereof. Such pharmaceutically acceptable acid addition salts may be formed with organic or inorganic acids and include, for example, the acetates, succinates, tartrates, citrates, hydrochlorides, hydrogen sulphates, and sulphates of the bases of formula I.

The compounds of the present invention may be administered orally, rectally or parenterally, preferably orally. In use, the compounds of the present invention are administered in conventional formulations and thus the present invention also provides therapeutic compositions which comprise as an active ingredient a compound of the hereinbefore defined formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier. harmaceutically acceptable carriers suitable for use in the preparation of compositions suitable for oral, rectal or parenteral administration are well known in the art of pharmacy.

The compositions of the present invention suitably contain 0.1 90% by weight of active ingredient.

Compositions for oral administration are the preferred compositions of the invention, and these are the known pharmaceutical forms for such administration,

for example, tablets, capsules, syrups and aqueous and oily suspensions. The excipients used in the preparation of these compositions are the'excipients known in the pharmacists art. Tablets may be prepared by mixing the active ingredient of the present invention with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and

lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. Suchtablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly capsules, for example hard or soft gelatin capsules, containing a compound of the present invention with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 10 500 mg. of a compound of the present invention. Other compositions for oral administration include, for example, aqueous suspensions containing a compound of the present invention in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.

Compositions of theinventionsuitable for rectal administration are the known pharmaceutical forms for such administration, for example suppositories with cocoa butter or polethylene glycol bases.

Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.

The compositions'of the present invention may be made up in a dosage unit form suitable for the particular mode of administration to be used. For example, the dosage unit may exist in the form of a tablet, capsule or syrup suitable for oral administration, a suppository suitable for rectal administration, or a solution or suspension suitable for parenteral administration.

The present invention also provides a method of treating depression in warm-blooded animals, including man, which comprises the administration of a therapeutically effective dose of a compound of the hereinbefore defined formula I or a pharmaceutically acceptable acid addition salt thereof. A suitable dosage is generally within the range 0.05 50 mg./kg./day, more usually 01 25 mg./kg./day, and especially 0.5 l5 mg./kg./day, given in single or divided doses.

The compounds of the present invention may be prepared by a process which comprises reacting pyrrolidine with a compound of the formula II wherein R is hydrogen or methoxy.

The intermediate compounds of formula 11 may be prepared, for example, by reacting a 2- methylsulphonyl--R-benzothiazole with 4-(2-chloroewherein R represents hydrogen, halogen, lower alkyl containing up to 4 carbon atoms, trifluoromethyl, alkoxy or nitro and R and R are the same or different and represent hydrogen, lower alkyl containing up to 4 carthoxy)aniline. The reaction is suitably effected by heat- 5 be atoms, p-1 d thy] or benzyl, except when R, ing the reactants together in asuitable inert organic solis hydrogen and R2 and R3 are at the Same time both Vent, for example toluenelower alkyl; or NR R represents a piperidino, morpho- Another process for preparing the compounds of the lino or 4 methy]piperidino group present invention comprises reacting 4-(2-pyrrolidin-1- The compounds f f l I Possess a high level of ylethomphenyl isothiocyanate with a compound of activity (hereinafter referred to as antireserpine activthe formula ity) in the hereinbefore mentioned reversal of reser- 1 pine-induced hypothermia test in mice, combined with R 2 a low level of undesirable side effects, and in this ad- (III) vantageous combination of properties the compounds of formula I exhibit the superior pharmacological pro- SH files referred to above.

Thus the compound 2-[4-(2-pyrrolidin-l-ylethoxin which R is as hereinbefore defined. The reaction is y )al filinolbex,lzoxaz9le referred which has a suitably effected by heating the reactants in a suitable similar level of antlreserpme to those of the inert organic Solvent, for example t01uene compounds of formula I, has been shown to be mark- The compounds of the present invention produced e dly teraufgeniF m rats P f whereas f by the reactions described above may be isolated as tlve tests in animals at similar dosages levels with the free bases or as pharmaceutically acceptable acid addi- Compounds of formul? I (rats for compound Rzhy" tion salts thereof by means of conventional techniques. drogen; and rabbts for fP Rzmethoxy) Similarly the free base compounds of the present inven gave no evldence of teratogemcty' Furthermore the i may be Converted to pharmaceutically acceptable compounds of formula 1 have superior antireserpine acacid addition salts thereof by reacting the appropriate tiYities E that the mp b and acid together in a Suitable organic solvent for diethylammoethoxy)an1lmo]benzoth1azole referred to example ethanol, as the reaction medium. above. Also the latter compound possesses an undesir- A property possessed by antidepressants is that part ably high level of amphetamine-like CNS Stimulant of reversing reserpine-induced hypothermia in stantivity Show" y the fact that in cats it Produces dard laboratory animals such as mice. A test to evalu- Phfiliaminolike stereotyped reactions), in contrast to ate this property was carried out with the compounds the Compounds of formula which, in Comparative tests f f l I (R or CH3O) The test was carried out at similar dosage levels, did not cause these stereotyped i i as d ib d b Shadbolt et in Med reactions. Another compound which, at similar dosage Chem. vol. 14 p. 837 (1971), and thefollowing results levels, causes amphetamine-like stereotyped reactions were obtained, in cats is 2-[4-(2-piperidin-1-ylethoxy)anilino]benzothiazole, a compound which is specifically exemplified in British Patent Specification No. 1,153,648. This R ED (median effective compound has a similar antireserpine activity to those dose) in mgjkg' of the compounds of formula l The remaining com- H 3,7 pounds specifically exemplified in British Patent Specia fication No. 1,153,648 have inferior antireserpine activities to those of the compounds of formula 1. As shown by tests in standard laboratory animals, the The following non-limitative examples illustrate the compounds of formula I surprisingly possess superior invention. pharmacological profiles as antidepressants in compar ison with a variety of chemically related compounds, including 2-[4-(2-pyrrolidin-l-ylethoxy)anilino]ben- 5O EXAMPLE 1 zoxazole (known from British Patent S ecification No. 1,153,647 as a compound with antidegressant proper- 4'(2 ChlomethOXy)amlme ties), 2-[4-(2-diethylaminoethoxy)anilino]benzo- A Soilltion of Z-hydwXyethOXy)acetanilide thiazole (known from British Patent Specification No. g-), chloroform litres) and dimethylformamide 1,034,538 as a compound with hypocholesterolaemic is Stirred and oo ith ce ater during properties), and the anilinobenzothiazoles specifically addition of a Solution of thionyl Chloride (475 ml.) in exemplified in British Patent Specification N0. chloroform (720 ml.) during 45 minutes. The solution 1,153,648. The latter specification is concerned with a is then boiled under reflux for about 2.5 hours, one to group of anilinobenzothiazoles with antidepressant two litres of chloroform distilled off at atmospheric properties and there are claimed compounds of the pressure and most of the remainder at reduced presgeneral formula IV sure. The residue is treated with water (5,6 litres) and R s NH ocn u-i nn n v L heated to remove residual chloroform. Concentrated hydrochloric acid (5.42 litres) is then added and the mixture boiled under reflux for one hour. The hot solution is filtered and the hydrochloride collected from the cooled filtrate. A solution of the hydrochloride in water (7.5 litres) at 60C. is stirred and treated gradually with ammonia solution (density 0.88, 350 ml.) to precipitate the product which is filtered off from the cooled mixture, washed with water and dried to give 4-(2-chloroethoxy)aniline, m.p. 9l 92C.

B. -Methoxy-2-[4-(2-chloroethoxy)anilinolbenzothiazole A mixture of 5-methoxy-2-methylsulphonylbenzothiazole (1,105 g.), 4-(2-chloroethoxy)aniline (780 g.) and toluene (5 litres).is boiled for 2 hours under reflux with simultaneous removal of water. A further quantity of 4-(2-chloroethoxy)aniline (156 g.) is then .added and the mixture boiled under reflux for 4 hours. The mixture is cooled, the solid filtered off, washed with ethanol (about 3 litres) and-dried to give 5-methoxy-2- [4-(2-ch1oroethoxy)anilino]benzothiazole m.p. 176 178C.

C. .5-Methoxy-2-[4-( 2-pyrrolidinl -ylethoxy)anilino]benzothiazole 1 A mixture of 5-methoxy-2-[4-(2-chloroethox y)anilino]benzothiazole (200 g.), pyrrolidine 144 ml.) and 2-methoxyethanol (1 litre) is boiled under reflux for 16 hours. The mixture is evaporated from the steam loath at reduced pressure and the residue dissolved in approximately 2N'hydr0chloric acid. The solution is washed with ethyl acetate, basified with 40% sodium hydroxide solution and extracted-with chloroform. The chloroform is washed with water, dried over magnesium sulphate and passed through a column of alumina. The column is washed with chloroform and the combined chloroform solutions evaporated. The residue is recrystallised from 2-methoxyethanol to give 5- methoxy-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]benzothiazole, m.p. 167 168C.

in an analogous manner to thatdescribed above there are prepared 2-[4-(2-pyrrolidin-l-ylethoxy)anilino]-benzothiazole, m.p. l35.5 137C. and the intermediate compound 2-[4-(2-chloroethoxy)anilino lbenzothiazole, m.p. 173 174C.

EXAMPLE 2 A. 4-( 2-Pyrrolidinl -ylethoxy)phenyl isothiocyanate 4-(2-Pyrrolidin-l-ylethoxy)aniline (17.3 g.) in ethanol (20 ml.) is added dropwise to a mixture of ethanol (55 ml.), carbon disulphide ml.) and aqueous ammonia (density 0.88, ml.) at 0C. After 2 hours the solid is collected and washed with acetone, m.p. 143 150C. (dec.). This solid (23.6 g.), chloroform (114 ml.) and triethylamine (l 1.9 ml.) are stirred, and ethyl chloroformate (8.6 ml.) added with cooling so that the temperature remains below 0C. After stirring for minutes below 0C. and 1 hour at 20C., excess of 10% sodium hydroxide is added. The chloroform is separated, washed with water, dried and evaporated. The residue is dissolved in benzene and the solution filtered through alumina. The filtrate is evaporated and the residue distilled to give 4-(2-pyrrolidin-l-ylethoxy)phenyl isothiocyanate, b.p. 160 168C./0.2 mm.

The isothiocyanate forms a hydrochloride, m.p. 149 150C. (from chloroform/petroleum ether b. p. 60 80C.)

- p -B. V

5 Methoxy-2-[4-(2-pyrrolidin-lylethoxy)anilino]benzothiazole Triethylamine (0.7 ml.) is added to a suspension of 2-amino-4-methoxybenzenethiol hydrochloride (0.96 g.) in toluene (20 ml.) under nitrogen. 4-(2-Pyrrolidin- 1-ylethoxy)phenyl isothiocyanate (1.24 g.) is added and the mixture stirred and heated under reflux for 16 hours. Ethylacetate and 10% sodium hydroxide are added and the organic layer separated, washed with water and dried. The organic layer is passed through a column of silica gel (2 X '20 cm.) and the filtrate rejected. The column is eluted with methanol, which, on concentration gives 5-methoxy-2-[4-(2-pyrrolidin-lylethoxy)anilino]benzothiazole, m.p. 167 cC.

In a similar manner there is prepared the compound 2-[4-( 2-pyrrolidinl -yleth ox y)anilino1benzothiazole m.p. 135.5 137C.

EXAMPLE ,3

A. A solution of 5-meth'oxy-2-[4-(2-pyrrolidin-lylethoxy)anilino]benzothiazole (0.369 g.) in ethanol (14 ml.) is treated at room "temperature with a solution of dry hydrogen chloride in ethanol (0.37 ml. of 10% w/v solution) and the mixture kept at room temperature for 24 hours. The precipitate which forms is collected by filtration, washed with dry ether and dried to give 5-methoxy-2-[4-(2-pyrrolidinl ylethoxy)anilino]benzothiazole hydrochloride hemihydrate, m.p. 196 199C. with previous softening. Elemental analysis satisfactory for C l-l ClN 0 S. /zH 0.

B. A hot solution of 5-m ethoxy-2-[4-(2-pyrrolidin-lylethoxy)anilino]benzothiaiole (0.738 g.) in ethanol m1.) is treated with a hot solution of citric acid (0.384 g.) in ethanol(2.5 ml.). The solution is allowed to cool to room temperature and then kept at 0 10C. overnight. The precipitate which forms is collected by filtration, washed with ethanoland dried to give 5- methoxy-2- [4-( 2-pyrrolidin l -ylethoxy )anilino benzothiazole citrate, m.p. 156C'.(dec.) with'previous softening. Elemental analysis satisfactory for EXAMPLE 4 pared:

A. Hydrochloride, m.p. 205 207C. with previous softening. Elemental analysis satisfactory for c m cm os.

B. Bis 2-[4-(2-pyrrolidin-l-ylethoxy)anilino]benzothiazole succinate, m.p. l86 187C. Elemental analysis satisfactory for C H N S EXAMPLE 5 In the preparation of tablets, the following mixture is dry granulated and compressed in a tableting machine to give tablets containing 25 mg. of active ingredient:

5-Methoxy-2-l4-(2-pyrrolidinl-ylethoxy)anilino]benzothiazole l0 g. lactose 5 g. calcium phosphate 5 g. maize starch 5 g.

In a similar manner tablets are prepared containing mg. of active ingredient.

EXAMPLE 6 In a preparation of enteric coated tablets, the tablets described in Example 5 are given a thin coat of shellac varnish followed by 20 coats of cellulose acetate phthalate.

EXAMPLE 7 In the preparation of capsules, a mixture of the ingredients described in Example 5 is encapsulated in hard gelatin capsules to give capsules containing 25 mg. of active ingredient. Enteric coating is applied by conventional dipping in cellulose acetate phthalate.

Capsules containing 10 mg. active ingredient are prepared in a similar manner.

EXAMPLE 8 In a preparation of capsules, a mixture of equal parts by weight of 5-methoxy-2-[4-(2-pyrrolidin-lylethoxy )anilino]benzothiazole and calcium phosphate is encapsulated in hard gelatin capsules, each capsule containing 25 mg. active ingredient.

Capsules containing 10 mg. active ingredient are prepared in a similar manner.

\ EXAMPLE 9 In the preparation of enteric coated capsules, the

capsules of Example 8 are coated with cellulose acetate phthalate in a conventional manner.

EXAMPLE l0 Suppositories weighing 1 g. and containing 25 mg. of 5-methoxy-2-[4-( 2-pyrrolidinl -ylethoxy )anilino]- benzothiazole are prepared in a conventional manner using a base consisting of:

polyethylene glycol 4000 33 polyethylene glycol 6000 47 water 20 Suppositories weighing 1 g. and containing 50 mg. of active ingredient are prepared in a similar manner.

EXAMPLE 1 l Compositions analogous to those described in Examples 5 10 are prepared using 2-[4-(2-pyrrolidin-lylethoxy)-anilino]benzothiazole as the active ingrediem.

I claim:

1. A benzothiazole compound selected from the group consisting of a compound of the formula NH OCHZCHZ-N S thiazole. 

1. A BENZOTHIAZOLE COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 wherein R is methoxy.
 3. 5-Methoxy-2-(4-(2-pyrrolidin-1-ylethoxy)anilino)-benzothiazole.
 4. 2-(4-(2-Pyrrolidin-1-ylethoxy)anilino)benzothiazole. 